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Low-Dose LPS Modulates Microglia/Macrophages Phenotypic Transformation to Amplify Rehabilitation Effects in Chronic Spinal Cord Injured (CSCI) Mice

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Abstract

Spinal cord injury (SCI) results in stalled motor function recovery under the chronic phase. One of the reasons due to the presence of ongoing inflammation. Therefore, regulating the status of immune cells may help reopen the window for neural repair, which represents a potential therapeutic target. In this study, we aimed to investigate whether this could be achieved in mice with cervical 5 crush CSCI (4 W) by utilizing a concentration of 0.5 mg/kg of lipopolysaccharide (LPS) to stimulate microglia/macrophages. Additionally, the mice underwent rehabilitation training for another 6 weeks. Our results showed that systemic injection of LPS enhanced the effects of forelimb rehabilitation training, as evaluated through single pellet grasping (SPG). Electrophysiological studies revealed the restoration of cortical drive to the injured side’s forelimb muscles in the training combined with LPS group. Tract tracing studies demonstrated the reconstruction of cortical innervation to the cervical spinal cord. Furthermore, the levels of pro-inflammatory phenotype markers, such as inducible nitric oxide synthase (INOS) and CD68, decreased, while the expression of anti-inflammatory phenotype markers, including arginase 1 (ARG-1) and CD206, increased. Importantly, this phenotypic switch in microglia/macrophages was accompanied by an increase in phagocytic activity markers as indicated by BODIPY + IBA1 + staining. Collectively, our data suggests that low-dose LPS improves the effects of rehabilitation training by regulating the phenotypic transformation of microglia/macrophages in CSCI. This study provides a fresh perspective and intervention direction for the clinical treatment of chronic spinal cord injuries.

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Data Availability

All data in the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

The authors sincerely appreciate the experimental platform support of the State Key Laboratory of Trauma, Burns and Combined Injury, Department of Research Institute of Surgery, Daping Hospital, Army Military Medical University. Botao Tan and Ying Yin were supported by the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University.

Funding

This work was supported by the National Natural Science Foundation for Youth Scholar of China (grant numbers: 82002377; 82302863), the Natural Science Foundation of Chongqing (grant numbers: cstc2020jcyj-msxm0651; CSTB2023NSCQ-MSX0160), as well as the Chongqing Municipal Science and Technology Bureau and Health Commission (grant numbers: 2020MSXM108; 2023MSXM037).

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  1. Juan Zhong is first author.

Authors and Affiliations

  1. Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China

    Juan Zhong, Yingxi He, Qin Zhao, Haodong Luo, Qing Zhang, Yu Tian, Ying Yin, Lehua Yu, Lu Pan & Botao Tan

  2. State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Yuan Liu & Ce Yang

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Contributions

Supervision, funding acquisition, and resources supporting: Ce Yang, Yuan Liu, Ying Yin,Botao Tan, Lehua Yu, and Lu Pan; study design, manuscript preparation and writing: Juan Zhong and Botao Tan; manuscript review: Botao Tan and Lu Pan; animal experiments, statistical collection and analysis: Juan Zhong, Yingxi He, Qin Zhao, Haodong Luo, Qing Zhang and Yu Tian. All authors read and approved the final manuscript.

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Correspondence to Lu Pan or Botao Tan.

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All animal experimental procedures were approved by the Animal Experimental Ethics Committee of Chongqing Medical University [(2020)161].

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Zhong, J., He, Y., Zhao, Q. et al. Low-Dose LPS Modulates Microglia/Macrophages Phenotypic Transformation to Amplify Rehabilitation Effects in Chronic Spinal Cord Injured (CSCI) Mice. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03979-y

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